P.1.d.002 Aggressive and hyperactive behavioural characteristics is increased in maternal social separated rat

Abstract

Lurasidone is a novel antipsychotic agent with high affinity for dopamine D2 and serotonin 5-HT7, 5-HT2A, and 5-HT1A receptors. We previously reported that in addition to its antipsychotic action, lurasidone shows beneficial effects on mood and cognition in rats, likely through 5-HT7 receptor antagonistic actions. In this study, we evaluated binding of lurasidone to 5-HT7 receptors in the rat brain by autoradiography using [3H]SB-269970, a specific radioligand for 5-HT7 receptors. Brain slices were incubated with 4 nM [3H]SB-269970 at room temperature and exposed to imaging plates for 8 weeks before phosphorimager analysis. Using this method, we first investigated 5-HT7 receptor distribution. We found that 5-HT7 receptors are abundantly localized in brain limbic structures, including the lateral septum, thalamus, hypothalamus, hippocampus, and amygdala. On the other hand, its distribution was moderate in the cortex and low in the caudate putamen and cerebellum. Secondly, binding of lurasidone, a selective 5-HT7 receptor antagonist SB-656104-A and an atypical antipsychotic olanzapine to this receptor was examined. Lurasidone, SB-656104-A (10–1000 nM), and olanzapine (100–10,000 nM) showed concentration-dependent inhibition of [3H]SB-269970 binding with IC50 values of 90, 49, and 5200 nM, respectively. Similar inhibitory actions of these drugs were shown in in vitro [3H]SB-269970 binding to 5-HT7 receptors expressed in Chinese hamster ovary cells. Since there was no marked species difference in rat and human 5-HT7 receptor binding by lurasidone (Ki = 1.55 and 2.10 nM, respectively), these findings suggest that binding to 5-HT7 receptors might play some role in its beneficial pharmacological actions in schizophrenic patients.